Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body:
1. Increased rate of protein synthesis in all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 L is NR.sup.6, O or CH.sub.2 ; PA1 m is 0 to 2; PA1 n is 0 to 2; PA1 q is 0 to 3; PA1 and pharmaceutically acceptable salts and individual diastereomers thereof. PA1 Z is --COCR.sup.1 R.sup.2c NHCOANR.sup.4 R.sup.5 PA1 A is --CR.sup.7 R.sup.7a (CH.sub.2).sub.y --; y is 0 to 3; PA1 and R.sup.2c is H or CH.sup.3 ; PA1 R.sup.7 is C.sub.1 -C.sub.3 alkyl; PA1 R.sup.7a is H or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.4 is hydrogen or C.sub.1 -C.sub.3 alkyl; or R.sup.4 and R.sup.7a are combined to form an alkylene bridge; PA1 m is one; PA1 R.sup.12 is hydrogen; PA1 R.sup.3a is hydrogen, F or Cl; PA1 T is phenyl, thienyl, thiazolyl, oxazolyl, isoxazolyl or pyrazolyl, each optionally substituted with one to three substituents, selected from F, OH, OCH.sub.3, OCF.sub.3, CF.sub.3 and CH.sub.3 ; PA1 R.sup.3b is hydrogen, C(O)NR.sup.8 R.sup.9, NHC(O)NR.sup.8 R.sup.9, NHS(O).sub.2 R.sup.9, NHC(O)R.sup.9 ; PA1 m is one; PA1 T is a bond; preferred within this class are those compounds wherein; PA1 R.sup.3a and R.sup.12 are hydrogen. PA1 R.sup.3b is CONR.sup.8 R.sup.9, SO.sub.2 NR.sup.8 R.sup.9, COOH, COO(C.sub.1 -C.sub.6)alkyl, NHSO.sub.2 R.sup.9, NHSO.sub.2 NR.sup.8 R.sup.9, NHC(O)NR.sup.8 R.sup.9, NHC(O)R.sup.9, NR.sup.8 R.sup.9 or OR.sup.8 ; PA1 R.sup.9 is hydrogen, phenyl, or thienyl optionally substituted with one to three substituents selected from F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; or R.sup.9 is C.sub.1 -C.sub.6 alkyl optionally substituted with one to three substituents selected from F, OH, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; or R.sup.8 ; PA1 R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, optionally substituted C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl where the substituents may be 1 to 5 halo or 1 to 3 hydroxy; or R.sup.8 and R.sup.9 can be taken together to form --(CH.sub.2).sub.r L.sub.a (CH.sub.2).sub.s -- wherein L.sub.a is C(R.sup.2).sub.2, O, S(O).sub.m or N(R.sup.2) where r and s are independently 1 to 3. PA1 n is zero; PA1 m is one; PA1 R.sup.3a is hydrogen; PA1 R.sup.12 is hydrogen; PA1 R.sup.3b is CONR.sup.8 R.sup.9, NHC(O)NR.sup.8 R.sup.9, NHS(O).sub.2 R.sup.9, SO.sub.2 NR.sup.8 R.sup.9, NHSO.sub.2 NR.sup.8 R.sup.9, NHCOR.sup.9 or OR.sup.8 ; PA1 R.sup.9 is phenyl, or thienyl optionally substituted with one to three substituents selected from F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; or R.sup.9 is C.sub.1 -C.sub.6 alkyl optionally substituted with one to three substituents selected from F, OH, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; and PA1 R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.3 -C.sub.7 cycloalkyl each optionally substituted with 1 to 5 halo or 1 to 3 hydroxy; or R.sup.8 and R.sup.9 can be taken together to form --(CH.sub.2).sub.n La(CH.sub.2).sub.s -- wherein La is C(R.sup.2).sub.2, O, s(O)m or N(R.sup.2) where r and s are independently 1 to 3. PA1 n is one; PA1 m is one; PA1 W is hydrogen; PA1 Y is hydrogen or methyl; ##STR10## M is --C(O)--; PA1 W is hydrogen; PA1 n and m are one; PA1 Y is phenyl-K, pyridyl, pyrimidyl, thienyl-K, or thiazolyl, C.sub.4 -C.sub.10 cycloalkyl, oxazolyl, phenyl-(C.sub.1 -C.sub.4 alkyl)-K-, thienyl-(C.sub.1 -C.sub.4 alkyl)-K- where K is O or is a bond and each of the above aryl groups is optionally substituted with one to three substituents independently selected from F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 X is R.sup.2 or --C(O)--NR.sup.8 R.sup.9 ; PA1 R.sup.9 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl each optionally substituted with one to three substituents selected from Cl, F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; PA1 R.sup.8 is hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C.sub.1 -C.sub.10 alkanoyloxy, 1 to 3 C.sub.1 -C.sub.6 alkoxy, phenyl, phenoxy, C.sub.1 -C.sub.6 alkoxycarbonyl, S(O).sub.m (C.sub.1 -C.sub.6 alkyl); or R.sup.8 and R.sup.9 can be taken together to form --(CH.sub.2).sub.r L.sub.a (CH.sub.2).sub.s -- where L.sub.a is C(R.sup.2).sub.2, O, S(O).sub.m or N(R.sup.2), r and s are independently 1 to 3. PA1 Z is --COCR.sup.1 R.sup.2c NHCOANR.sup.4 R.sup.5 PA1 A is --CR.sup.7 R.sup.7a (CH.sub.2).sub.y --; y is 0 to 3; PA1 and R.sup.2c is H or CH.sub.3 ; PA1 R.sup.7 is C.sub.1 -C.sub.3 alkyl; PA1 R.sup.7a is H or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.4 is hydrogen or C.sub.1 -C.sub.3 alkyl; or R.sup.4 and R.sup.7 are combined to form an alkylene bridge; PA1 R.sup.5 is hydrogen or C.sub.1 -C.sub.3 alkyl optionally substituted with one or two hydroxyl groups; PA1 R.sup.1 is selected from the group consisting of 1-indolyl-CH.sub.2 -, 2-indolyl-CH.sub.2 -; 3-indolyl-CH.sub.2 -, 1-naphthyl-CH.sub.2 -, 2-naphthyl-CH.sub.2 -, 1-benzimidazolyl-CH.sub.2 -, 2-benzimidazolyl-CH.sub.2 -, phenyl-C.sub.1 -C.sub.4 alkyl-, 2-, 3- or 4-pyridyl-C.sub.1 -C.sub.4 alkyl, phenyl-CH.sub.2 -S-CH.sub.2 -, thienyl-C.sub.1 -C.sub.4 alkyl, and phenyl-(CO-C.sub.3 alkyl)-O-CH.sub.2 -, phenyl-CH.sub.2 O-phenyl-CH.sub.2 -, and 3-benzothienyl-CH.sub.2 -, or any of the above groups substituted in the aryl portion with one to three F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3 or CF.sub.3 substituents; PA1 R.sup.2c is hydrogen; y=0; R.sup.7 and R.sup.7a are methyl and R.sup.4 and R.sup.5 are hydrogen and R.sup.1 is C.sub.6 H.sub.5 CH.sub.2 -O-CH.sub.2 -, phenyl-CH.sub.2 -S-CH.sub.2 -, 1-napthyl-CH.sub.2 -, 2-napthyl-CH.sub.2 -, phenylpropyl or, ##STR11## and the aryl portion of R.sup.1 is optionally substituted with fluorine, CH.sub.3 or CF.sub.3 ; and n is zero one; m is zero or one; Y is C.sub.4 -C.sub.10 cycloalkyl, phenyl, phenyl-CH.sub.2 -, phenyl-O-, pyridyl, pyrimidyl, thienyl, thienyl-CH.sub.2 -, thiazolyl or oxazolyl, each optionally substituted with one to three substituents independently selected from F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3, OCF.sub.2 H and CF.sub.3 ; X is H, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkyl substituted with one to five fluorine atoms; W is hydrogen. PA1 Z is --COCR.sup.1 R.sup.2c NHCOANR.sup.4 R.sup.5 PA1 A is --CR.sup.7 R.sup.7a (CH.sub.2).sub.y ; y is 0 to 3; PA1 and R.sup.2c is H or CH.sub.3 ; PA1 R.sup.7 is C.sub.1 -C.sub.3 alkyl; PA1 R.sup.7a is H or C.sub.1 -C.sub.3 alkyl; PA1 R.sup.4 is hydrogen or C.sub.1 -C.sub.3 alkyl; or R.sup.4 and R.sup.7a are combined to form an alkylene bridge; PA1 R.sup.5 is hydrogen or C.sub.1 -C.sub.3 alkyl optionally substituted with one or two hydroxyl groups; PA1 R.sup.1 is selected from the group consisting of 1-indolyl-CH.sub.2 -; 2-indolyl-CH.sub.2 -; 3-indolyl-CH.sub.2 -; 1-naphthyl-CH.sub.2 -; 2-naphthyl-CH.sub.2 -; 1-benzimidazolyl-CH.sub.2 -; 2-benzimidazolyl-CH.sub.2 -; phenyl-C.sub.1 -C.sub.4 alkyl-; 2-, 3- or 4-pyridyl-C.sub.1 -C.sub.4 alkyl; thienyl-C.sub.1 -C.sub.4 alkyl; phenyl-(CH.sub.2).sub.n -O-CH.sub.2 - where n is zero to three; phenyl-CH.sub.2 O-phenyl-CH.sub.2 -; and 3-benzothienyl-CH.sub.2 -; or any of the above groups substituted in the aryl portion with one to three F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3 or CF.sub.3 substituents; PA1 Y is hydrogen and X is: ##STR12## wherein n and m are one and A.sup.1 is a bond and W is hydrogen; or X is: ##STR13## wherein R.sup.3a is hydrogen, F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3 or CF.sub.3 ; PA1 R.sup.12 is hydrogen, F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3 or CF.sub.3 ; PA1 R.sup.aa is hydrogen, C.sub.1 -C.sub.8 alkyl optionally substituted with one to three halogens; or phenyl optionally substituted with one to three substituents independently selected from halogen, CH.sub.3, OCH.sub.3, OCF.sub.3, CF.sub.3 and C.sub.1 -C.sub.8 alkyl aryl; PA1 R.sup.bb is hydrogen, C.sub.1 -C.sub.8 alkyl, optionally substituted with one to three substituents independently selected from halogen, CH.sub.3, OCH.sub.3, OCF.sub.3, CF.sub.3 ; C.sub.3 -C.sub.8 cycloalkyl; phenyl optionally substituted with one to three substituents independently selected from halo, CH.sub.3, OCH.sub.3, OCF.sub.3 or CF.sub.3 ; --O--C.sub.1 -C.sub.8 alkyl; or --S--C.sub.1 -C.sub.8 alkyl. PA1 a method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of a compound of Formula I; PA1 a composition useful for increasing the endogenous production or release of growth hormone in a human or an animal which comprises an inert carrier and an effective amount of a compound of Formula l; PA1 a composition useful for increasing the endogenous production or release of growth hormone in a human or an animal which comprises an inert carrier and an effective amount of a compound of Formula I used in combination with other growth hormone secretagogues such as, GHRP-6, Hexorelan, GHRP-1, growth hormone releasing factor (GRF) or one of its analogs or IGF-1 or IGF-2, or B-HT920; and PA1 a method for the treatment of osteoporosis which comprises administering to a patient with osteoporosis a combination of a bisphosphonate compound such as alendronate, and a compound of Formula I.
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
It is now widely recognized that most human growth deficiencies are due to hypothalamic defects that impair the release of pituitary growth hormone and are not the result of a primary deficit in the production of growth hormone by the pituitary. As a result, the development of synthetic growth hormone-releasing agents and the use of drugs acting through established neurotransmitter systems in the brain to stimulate growth hormone release are being considered as alternatives to highly expensive growth hormone replacement therapy for the restoration of normal serum growth hormone levels. Strobel and Thomas, Pharm. Rev. 46, No. 1, pg. 1-34 (1994).
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low.
WO 94/13696 refers to certain spiropiperidines and homologs which promote release of growth hormone. Preferred compounds are of the general structure shown below. ##STR2##
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure ##STR3## where L is ##STR4##
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.